Amphiphilic block copolymers having optimal hydrophilic and hydrophobic segments self-assemble spontaneously in aqueous environment forming micelles or supramolecular assemblies. These supramolecular assemblies exhibit core-shell architecture wherein the hydrophobic part forms the core and the hydrophilic part forms the corona. Recently, polymeric micelles have been widely used as drug delivery carriers for parenteral administration. Micellar drug delivery carriers have several advantages including biocompatibility, solubilization of hydrophobic drugs in the core, nanometric size ranges which facilitate extravasation of the drug carrier at the site of inflammation, site-specific delivery etc. (see for example Torchilin VP, J Controlled Release, 2001, 73 137–172; Kataoka et al, Adv Drug Deliv Rev, 2001, 47, 113–131; Jones et al, Eur J Pharm Biopharm, 1999, 48, 101–111).
A large number of amphiphilic block copolymers, having nonionic and/or charged hydrophobic and hydrophilic segments, that form micelles are reported in the literature. Examples of some widely used block copolymers for parenteral delivery include poly(ethylene oxide)-b-poly(D,L-lactide), poly(ethylene oxide)-b-poly(ε-caprolactone), poly(ethylene oxide)-b-poly(aspartic acid), poly(N-vinyl pyrrolidone)-b-poly(D,L-lactide) etc.
U.S. Pat. No. 6,322,805 describes polymeric drug carrier micelles prepared from amphiphilic block copolymer having a hydrophilic poly(alkylene oxide) component and a biodegradable hydrophobic component selected from a group consisting of poly(lactic acid), poly(lactic-co-glycolic acid), poly(ε-caprolactone) and a derivative thereof. These micelles are capable of solubilizing hydrophobic drug in a hydrophilic environment.
U.S. Pat. No. 6,338,859 describes polymeric micelle compositions where the hydrophilic component includes poly(N-vinyl-2-pyrrolidone) and the hydrophobic component is selected from a group consisting of polyesters, polyorthoesters, polyanhydride and derivatives thereof. The polyester group can be selected from poly(D,L-lactic acid), poly(glycolic acid), lactide/glycolide copolymers, poly(s-caprolactone) and derivatives thereof. The micelle composition contains a therapeutic agent which can be an antitumor compound, hydrophobic antibiotic, hydrophobic antifungal agent, an immunomodulator, an antiviral drug, or the like.
U.S. Pat. No. 6,383,811 describes formation of complexes of polyions such as DNA with polyampholytes i.e. polymers possessing both cationic and anionic moieties, and delivery of the complex into the cell.
U.S. Pat. No. 6,210,717 describes a composition composed of mixed polymeric micelles made of amphiphilic polyester-polycation copolymer and an amphiphilic polyester-sugar copolymer for delivery of nucleic acids into targeted host cells. The polyester-polycation forms an electrostatic interaction with polyanionic nucleic acids, and the polyester-sugar copolymer directs the micelle-nucleic acid complex to cells in vivo.
U.S. Pat. No. 6,429,200 describes delivery of polynucleotides to cells using cleavable reverse micelles. Other molecules such as polymers, and surfactants containing disulphide linkages can be included into the complex micelles to enhance the delivery.
U.S. Pat. No. 5,510,103 describes block copolymers having the hydrophilic and hydrophobic segments forming micelles and entrapping the hydrophobic drugs by physical methods. The hydrophilic segment is preferably poly(ethylene oxide) and hydrophobic segment is preferably poly(ε-benzyl-L-aspartate) while the preferred drug is adriamycin.
U.S. Pat. No. 5,955,509 describes use of poly(vinyl-N-heterocycle)-b-poly(alkylene oxide) copolymers in micelle containing pharmaceutical formulations. These copolymers respond to pH changes in the environment and can be used to deliver therapeutic compounds at lower pH values. The micelles of these polymers remain intact at neutral pH, e.g. at physiological pH, while they will release the contents when exposed to a lower pH environment such as in the tumor.
U.S. Pat. No. 6,497,895 describes hyperbranched micelles containing a core of mucic acid esters for the encapsulation of hydrophobic molecules. These polymers are useful for the transdermal delivery of the entrapped agent in a controlled manner.
U.S. Pat. No. 6,387,406 describes compositions of the poly(oxyethylene)-poly(oxypropylene) block copolymers for oral delivery of biological agents.
Nishiyama et al (Pharm Res 2001, 18, 1035–1041; J Controlled Release 2001, 74, 83–94) have described the use of poly(ethylene oxide)-b-poly(α,β-aspartic acid) block copolymers forming micelles by interaction with an antitumor drug, specifically cisplatin.
Though the majority of these polymers can be used for oral delivery of bioactive agents, what is presently lacking are amphiphilic polymers capable of forming supramolecular assemblies that respond to an environmental stimuli such as pH change, thereby entrapping the contents in the micelle core at a low pH, such as that prevailing in the stomach, and rapidly releasing the contents at a higher pH, such as that prevailing in the intestine.
In our earlier filed U.S. patent application (Ser. No. 09/877,999, Jun. 8, 2001) we describe a series of ionizable diblock copolymers useful for the delivery of bioactive agents. A series of the polymers in this patent application partially fulfills the above requirement. These polymers are different from those disclosed in U.S. Pat. No. 5,955,509 in that they form supramolecular assemblies at low pH, that could be dissociated upon increase in the pH above pKa of the carboxyl group. Another characteristic of these polymers is the presence of nonionizable and reversibly ionizable groups in the hydrophobic segment, where, hydrophobicity can be changed by controlling the ionization.